Progress and Prospects in Parkinson's Research/Causes/Infection/Influenza

Influenza is a rapidly mutating virus with the potential to bring about a catastrophic pandemic. The 1918 outbreak of Spanish flu killed more people than died in the whole of World War I.  The H5N1 variety carries a 60% mortality rate. An analysis of the likelihood and impact of a flu pandemic on the UK population was issued in June 2012. And the current winter flu plan is available at http://www.rcm.org.uk/EasySiteWeb/GatewayLink.aspx?alId=232009.

In February 2012 the World Health Organization issued a guideline on vaccines for use in the 2012-2013 northern hemisphere influenza season It is recommended that they should contain the following: •	an A/California/7/2009 (H1N1)pdm09-like virus; •	an A/Victoria/361/2011 (H3N2)-like virus; •	a B/Wisconsin/1/2010-like virus. There is a growing body of evidence that influenza can prime the SN immune system so as to make it susceptinle to PD. This can happen prenatally.

Research
1977

Moore reviewed the evidence for a link between flu infection and the onset of PD:-

"Most investigators agree that many if not most cases of Parkinson's disease are a result of viral infection and that the 1918–19 influenza epidemic is of significance."

1988

Mattock et al compared the incidence of PD with flu outbreaks:-

"Patients with idiopathic Parkinson's disease do not appear to be distributed smoothly with respect to year of birth. Individuals born within the years 1892, 1904, 1909, 1918, 1919 and 1929 appear to have had an increased risk of developing idiopathic Parkinson's disease in later life. These years are close to those of the influenza pandemics of the period 1890-1930. The estimated risk of an individual developing idiopathic Parkinson's disease shows a significant correlation with the crude influenza mortality for the year of his birth, within the range 1900 to 1930. It is suggested that intra-uterine influenza may be cytotoxic to the developing foetal substantia nigra, and that an affected individual may be born without evident disability but with limited striatal neurochemical reserves and a reduced nigral cell count. In later life normal cellular involution with ageing or exposure to environmental neurotoxic factors may further erode these reserves to a level where the substantia nigra fails and idiopathic Parkinson's disease becomes clinically apparent."

1989

Ebmeier et al failed to validate claims of a linkage between PD and influenza.

"A study is presented which fails to replicate a recent report that peak years of birth of patients later developing Parkinson's disease are related to the influenza pandemics of the period 1890-1930. The years of birth of a whole population cohort of 243 patients suffering from Parkinson's disease examined in Aberdeen in 1983 and reexamined in 1986/7 were compared with deaths due to influenza in the City of Aberdeen in the years 1900-1930. Although a significant peak of Parkinson births (compared with the age profile of the Aberdeen population in 1983) occurred in 1902, there appeared to be no systematic relationship between Parkinson births and influenza deaths. In addition, no season of birth effect could be detected in a comparison with 232 matched controls. The presence of peaks of birth years, for whatever aetiological reason, is of significance to epidemiological studies in that prevalence estimates may be influenced by the year of study relative to these mini-cohorts."

1999

Takahashi and Yamada found evidence to support the hypothetical causal connection between PD and certain strains of flu virus. " Some clinical reports and epidemiological data suggest that a virus may play a role in the etiology of Parkinson's disease (PD). Once a certain strain of influenza A virus has adapted to the central nervous system, it will gain infectivity to neurons, especially in the substantia nigra, cerebellum and hippocampus, both in human cases and experimental models. Although efforts to detect virus particles in the brains, or antibodies in the serum or cerebrospinal fluid of patients with PD have been generally unsuccessful, recent immunohistochemical work has revealed the presence of complement proteins and the interferon-induced MxA in association with Lewy bodies and swollen neuronal process. We propose a hypothesis that neurovirulent influenza A virus and other potent viruses may be responsible for the formation of Lewy bodies and the later death of nigral neurons, to constitute a viral etiology for PD. "

2009

Jang et al presented evidence of a link between the H5N1 strain of influenza and PD:-

"One of the greatest influenza pandemic threats at this time is posed by the highly pathogenic H5N1 avian influenza viruses. To date, 61% of the 433 known human cases of H5N1 infection have proved fatal. Animals infected by H5N1 viruses have demonstrated acute neurological signs ranging from mild encephalitis to motor disturbances to coma. However, no studies have examined the longer-term neurologic consequences of H5N1 infection among surviving hosts. Using the C57BL/6J mouse, a mouse strain that can be infected by the A/Vietnam/1203/04 H5N1 virus without adaptation, we show that this virus travels from the peripheral nervous system into the CNS to higher levels of the neuroaxis. In regions infected by H5N1 virus, we observe activation of microglia and alpha-synuclein phosphorylation and aggregation that persists long after resolution of the infection. We also observe a significant loss of dopaminergic neurons in the substantia nigra pars compacta 60 days after infection. Our results suggest that a pandemic H5N1 pathogen, or other neurotropic influenza virus, could initiate CNS disorders of protein aggregation including Parkinson's and Alzheimer's diseases."

2011

Rohn and Catlin presented immunohistochemical data indicating the presence of influenza A virus within the substantia nigra pars compacta (SNpc) from postmortem PD brain sections.

"Influenza A virus labeling was identified within neuromelanin granules as well as on tissue macrophages in the SNpc. Further supporting a role for neuroinflammation in PD was the identification of T-lymphocytes that colocalized with an antibody to caspase-cleaved Beclin-1 within the SNpc"

2012

H.V. et al carried out a study in Belgrade from 2001 to 2005 using 110 cases of PD and 220 controls,

"According to logistic regression analysis PD was significantly related to … influenza, (odds ratio adjusted on occupation and history of PD = 8.01, 96% confidence interval 95% CI = 4.61 -13.92)."

Jang et al evaluated the effects on the central nervous system of mice infected with the H5Ni variant of  the influenza virus.

"Our findings therefore suggest that any neurotropic influenza virus that activates the immune system in the brain, whether directly or indirectly, could contribute to CNS disorders of protein aggregation; and more generally that viruses may be an important etiological agent in the developmental sequalae of neurodegenerative diseases including Parkinson’s disease."

2013

Estupinan et al disproved claims that PD would die out spontaneously as flu epidemics subsided.